As Manguso was wrapping up his PhD work in 2017, he, Haining (now at Arsenal Biosciences), and Kathleen Yates, an immunologist in Haining’s lab with a track record of executing large, complex projects, began to think big about the approach they were taking to discover new immunotherapy targets. They talked about how they might expand Manguso’s approach to cover the entire genome. Could they test the effect of every gene, in every cancer, to find every mechanism of resistance to immunotherapy?

“We wanted to see whether there were as yet undiscovered drug targets that would lead to amazing cancer immunotherapies,” Manguso said.

Together, Haining, Manguso, and Yates went on to found the Tumor Immunotherapy Discovery Engine (TIDE) at the Broad Institute of MIT and Harvard in 2017 with support from Calico as a collaborating partner. Today, Manguso and Yates co-lead a team of 22 systematically working towards Manguso’s goal. They scaled up their CRISPR screening approach to look across the whole genome in lab animals. Using that technology, they have already probed the role of every gene in immunotherapy resistance across eight cancer models. They’ve developed a new method to improve CRISPR screens in animal models, and have identified several new mechanisms of immune evasion shared by multiple cancers. 

Calico, together with AbbVie, has worked with TIDE to advance some of its drug discovery and development programs and now has projects — including the PTPN2 inhibitors — in various stages of preclinical and clinical development. Along the way, TIDE is showing how careful, systematic science at scale can quickly home in on promising drug targets.

“Every part of TIDE has been the fruit of collaboration and multidisciplinary team-based science,” Yates said. “Everybody just really wanted to help each other succeed. We’re deeply grateful for that.”

Studying the impact of a few thousand genes on a single cancer is challenging enough in an animal model. But scaling up those experiments in mice to probe the entire transcriptome — the expression of some 20,000 protein-coding genes — was another task entirely.

“We weren’t 100 percent sure we could do it,” Manguso remembered. “Most people would’ve considered even one of the experiments we were proposing to do basically impossible.”

Yates, however, was more confident. She’d been fascinated by immunology since middle school. After college, she spent two years working for a biotechnology company before joining Haining’s lab, where she rose through the ranks from technician to senior scientist. She’d helped Haining build his lab and manage large, ambitious projects, and had a good idea what it would take to scale up Manguso’s experiment.

When Manguso and Yates approached different scientists at Broad, they were struck by how excited everyone was by their idea. Together, they talked through all aspects of the project, such as how long it might take to optimize the technology, what the experiments might look like at scale, and how the researchers could measure progress.